Patent DE-10259407-A1 (DE)
Title: New bicyclic nitrogen-containing heteroaryl-substituted amides, are inhibitors of Factor Xa and/or related serine proteases, useful as antithrombotic agents, e.g. for treating or preventing deep leg vein thrombosis
IPC: C07D403/06
Filed: 2002-12-19
Abstract: N-Phenyl-(bicyclic nitrogen-containing heteroaryl)-acetamide or N-(bicyclic nitrogen-containing heteroaryl-methyl)-benzamide derivatives (I) are new.  Amides of formula (I) and their tautomers, diastereomers or enantiomers (or their mixtures) and salts are new.  R1  =  (i) NH2, alkylamino, -NH-Cyc or -NH-T-Ph (all optionally substituted (os) on N by COPh or SO2Ph or by alkyl or alkylcarbonyl (both os in the alkyl by COOH, Q, NH2, NHT, NT2 or 3-6C cycloalkyleneimino (CAI)), provided that N's are separated by at least two C's); (ii) dialkylamino or N-(Cyc)-alkylamino (where alkyls are os (but not in the 1-position) by OH, OT, NH2, NHT, NT2 or 3-8C CAI); (iii) 4-7 membered CAI-CO- or CAI-SO2- (where CAI is os by 1 or 2 of T, -T-OT, -T-NH2, -T-NHT, -T-NT2, -T-NHCOO-alkyl, -T-(3-6C) CAI, CONH2, CONHT, N-(Cyc)-alkylaminocarbonyl, N-(-T-Ph)-alkylaminocarbonyl or CONT2 or (on CH2 not adjacent to the imino) by OH, OCH2Ph, OT, NH2, NHT, NT2 or CAI; 5-membered CAI optionally has CH2 in the 3-position replaced by S, SO or SO2; 6- or 7-membered CAI optionally has CH2 in the 4-position replaced by O, S, NH, NT, N(2-3C alkanoyl), SO or SO2; and CH2CH2 in 5-7 membered CAI is optionally replaced by NHCO, CONH, CON(Me) or N(Me)CO); (iv) 5-7 membered cycloalkenyleneimino-CO- or cycloalkenyleneimino-SO2- (where the double bonded C is not bonded to N) (os by 1 or 2 of T, -T-NH2, -T-NHT, -T-NT2, -T-(3-6C) CAI, CONH2, CONHT, CONT2 or -CO-(3-6C) CAI); (v) CONH2 or SO2NH2 (both os by 1 or 2 alkyl, alkyls being os by 1 or 2 of os by 1 or 2 of T, -T-OT, -T-NH2, -T-NHT, -T-NT2, -T-(3-6C) CAI, -T-NHCOO-alkyl, -T-NH-(3-6C) cycloalkyl, CONH2, CONHT, N-(Cyc)-alkylaminocarbonyl, N-(-T-Ph)-alkylaminocarbonyl, CONT2 or -CO-(3-6C) CAI or (on CH2 not adjacent to NH) by OH, OCH2Ph, OT, NH2, NHT, NT2 or 3-6C CAI); (vi) (1-7C) alkylcarbonyl or Cyc-CO- (where CH2 in the 2-, 3- or 4-position of Cyc is optionally replaced by O, S, CO, SO, SO2, NH, NT or N(-CO-T)); (vii) Ph-CO- or Het-CO- (both os in the ring by F, Cl, Br, CF3, T, -T-NH2., -T-NHT, -T-NT2, -T-(3-6C) CAI or OT); (viii) T (os by NH2, NHT, NT2, OH, Ph, Het or 4-7 membered CAI (where Ph is os as in (vii); CH2CH2 in 5-7 membered CAI is optionally replaced by NHCO, CONH, CON(Me) or N(Me)CO; and CH2 not adjacent to N in 5-7 membered CAI is optionally replaced by CO)); or (ix) a polyaza- heterobicyclic group of formula (i) - (vii) (all os by CH2SO2Me, -T-NH2 or CONH2);  T  =  1-3C alkyl;  Cyc  =  3-7C cycloalkyl;  m  =  1 or 2;  R2  =  H, F, Cl, Br, T (os by one or more F), 2-3C alkenyl, 2-3C alkynyl, OT or OCF3;  R3, R5  =  H or T;  R4  =  H; alkyl (os by OH, OT, SH, ST, SOT, SO2T, COOH, CONH2, CONH2, CONHT, CONT2, -CO-(3-6C) CAI, NH2, NHT, NT2, (3-6C) CAI, NHCOT, (3-6C) cycloalkyl-CONH-, NHCOOCH2Ph or guanidino); Ph, Het, -T-Ph or -T-Het (all os by OH, OT, OCH2Ph, -O-T-COOH, -O-T-COOT, -O-T-CONH2, -O-T-CONHT, -O-T-CONT2, -O-T-(3-6C) CAI, COOH or COOT); -T-(4-7 membered) CAI; or -T-(4-7C) cycloalkyl (optionally having 1 or 2 ring CH2 replaced by NH or NT and optionally having 1 or 2 CH2 adjacent to NH or NT replaced by CO, provided that groups having two NH or NT groups separated by one CH2 are excluded);  or CR4R5  =  3-7C cycloalkylidene (optionally having one CH2 replaced by NH, NT, N(acyl) or sulfonylamino);  A  =  CONH, NHCO, CON(T) or N(T)CO;  B  =  benzimidazole, imidazo-pyridine, quinoline, indole or pyrrolo-pyridine group of formula (ix) - (xv);  n  =  1 or 2;  R6  =  H, T, OH, NH2 or NHT;  R7  =  H, F, Cl, Br, T (os by one or more F), 2-3C alkenyl, 2-3C alkynyl, OH, OT, OCF3 or CN;  Het  =  5-membered heteroaryl (containing as heteroatom(s) one NH, NT, N(-T-Ph), O or S (optionally together with one N); or one NH, NT or N(-T-Ph) plus 2 or 3 N) or 6-membered heteroaryl (containing 1-3 N heteroatom(s)), both os by T, COOH, COOT or NHCOOT and optionally fused with a benzo ring, Het being bonded via N or via C of the heterocycle or the benzo ring;  Q  =  group convertible to COOH in vivo, e.g. esterified carboxy, where the alcohol component is preferably a 1-6C alkanol, phenyl